Enf neuromusculares con fallo respiratorio

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N e u ro m u s c u l a rD i s o rde r s an d A c u t eR e s p i r a t o r y F a i l u re:Diagnosis andManagementKourosh Rezania, MDa,*, Fernando D. Goldenberg, MD a ,Steven White, MDb KEYWORDS Neuromuscular Respiratory failure ALS Myasthenia gravis Guillain-Barre CIDP Critical illness myopathy ´The diagnostic approach to a patient with respiratory failure starts with the determina-tion of whether the respiratory failure is the result of a cardiopulmonary disease versusa primary neurologic disorder. The latter can occur in the setting of either a centralnervous system (CNS) disease such as cervical myelopathy, lower brainstem injury,or diffuse bihemispheric involvement, or a neuromuscular disease (NMD). This reviewfocuses on NMDs that result in respiratory impairment because of weakness of therespiratory muscles. An NMD may result in respiratory weakness when there is impaired function of a largeproportion of the motor units that innervate the respiratory muscles. A motor unit isreferred to a motor neuron (located in the anterior horn cells of the spinal cord or themotor nuclei of the cranial nerves in the medulla and pons), its axon, and all the myofib-ers that it innervates (Fig. 1). Neuromuscular weakness may also result from diseasesthat primarily affect the myofiber plasma membrane or its contractile apparatus.1PATHOPHYSIOLOGYNMDs often present with acute or subacute respiratory weakness and a rapidlyevolving respiratory failure. On the other hand, the more indolent NMDs may also This work has not been supported by a grant. The authors have nothing to disclose. a Department of Neurology, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637, USA b Department of Medicine, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 6076, Chicago, IL 60637, USA * Corresponding author. E-mail address: krezania@neurology.bsd.uchicago.edu Neurol Clin 30 (2012) 161–185 doi:10.1016/j.ncl.2011.09.010 neurologic.theclinics.com 0733-8619/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.

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162 Rezania et al Fig. 1. A motor unit. (Courtesy of Netter Images; with permission.) present with an acute respiratory failure, which could be the result of disease progres- sion to a point that the compensatory mechanisms are overwhelmed, or emergence of a superimposed respiratory disease such as atelectasis, pneumonia (bacterial, viral or aspiration), or pulmonary embolism.

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Respiratory Failure in Neuromuscular Disease 163 NMDs may result in respiratory insufficiency with 3 potential mechanisms.2,3 Acombination of these mechanisms is often implicated in an individual patient:1. Weakness of the upper airway muscles. Weakness of the oropharyngeal muscles and tongue may result in impaired swallowing, which predisposes to aspiration of the food or respiratory secretions. Aspiration then results in atelectasis and pneumonia. Paralysis of the vocal cords and significant weakness of the tongue and pharyngeal muscles may also result in partial upper airway obstruction.2,42. Weakness of the inspiratory and expiratory muscles. The diaphragm, intercostal muscles, and accessory muscles are the main muscles of inspiration (Fig. 2). Weakness of these muscles may result in abnormal sigh mechanism, atelectasis caused by decreased lung expansion, and subsequent ventilation/perfusion (V/Q) mismatch. Hypoxemia may be the result of V/Q mismatch early in the course of the respiratory failure. The relative contribution of different inspiratory muscles changes in different positions. The diaphragm is the most important contributor in the supine position; therefore, diaphragmatic weakness is often associated with orthopnea. Progressive weakness of the inspiratory muscles leads to a decreased tidal volume. Compensatory tachypnea develops to maintain normal minute ventilation. This persistent tachypnea and increased work of breathing of the already weakened respiratory musculature may eventually lead to muscle exhaustion, with the evolving inability to maintain a normal minute ventilation,Fig. 2. Inspiratory and expiratory muscles. (Courtesy of Netter Images; with permission.)

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164 Rezania et al resulting in progressive hypercapnia and respiratory acidosis. Hypoxemia develops in an earlier stage of the respiratory failure than CO2 retention (hyper- capnia). The latter is usually present later in the course, and is associated with significant weakness and fatigue.5,6 Weakness of the expiratory muscles (ie, internal intercostals and abdominal muscles [see Fig. 2]), results in impaired cough- ing and clearance of respiratory secretions, which leads to mucous plugging, atel- ectasis, and pneumonia. Adequate strength of the inspiratory and expiratory muscles is essential for an effective cough. There should also be coordination between the muscles of the upper airways and the expiratory muscles so that the glottis opens during a forceful contraction of the expiratory muscles. 3. Concomitant cardiopulmonary disease. Patients with NMD often have a concomi- tant cardiomyopathy and congestive heart failure. They may also develop aspiration pneumonia and atelectasis, as mentioned earlier. The latter further decreases the lung compliance and increases the workload on the already weak muscles. Immobility may result in deep vein thrombosis and subsequent pulmo- nary embolization. Sleep exacerbates the hypoventilation associated with respiratory muscle weak- ness. The rapid eye movement (REM) stage is associated with hypotonia and flaccidity of the accessory muscles. Therefore, patients with diaphragmatic weakness may develop hypoxia and hypercapnia during the REM stage, if they sleep in the supine position. As the respiratory muscle weakness deteriorates, hypoventilation develops during the other stages of sleep, followed by wakefulness.7 GENERAL APPROACH TO A PATIENT WITH IMPENDING RESPIRATORY FAILURE When confronted with a patient with symptoms of respiratory failure, the first step is to secure the airways, provide adequate oxygenation and stabilize the hemodynamic status.1 It should be decided whether the patient has respiratory insufficiency, and if so, whether intubation and mechanical ventilation are needed. A short history often reveals the apparent cause (ie, a cardiopulmonary disease, a neurologic disorder, or a combination of both). The symptoms and signs that herald an impending respiratory failure include dysphagia, cough after swallowing, dysphonia, shortness of breath at rest or with minimal exertion, orthopnea, tachycardia, tachypnea, shallow breathing, use of accessory respiratory muscles, and paradoxic breathing. Weakness of the trapezius and the truncal muscles (including the neck flexors and extensors) is usually associ- ated with significant weakness of the diaphragm and other respiratory muscles. A single breath count test may be used to assess for poor respiratory reserve.2,3,6 Counting out loud in a single breath after a deep inspiration, an individual with a normal respiratory reserve can count to about 50. Being able to count to 25 and 10 roughly correlates with a forced vital capacity (FVC) of greater than 2L and 1L, respectively. Counts less than 15 are associated with substantial respiratory compromise.6 Stac- cato speech (interrupted talking) is another clinical evidence for low and impaired respiratory reserves. Dysphagia can be tested clinically by observing the patient after swallowing 88.7 mL (3 oz) of water. Coughing implicates the dysfunction of the upper airways, leading to the aspiration of oropharyngeal content, and the necessity of with- holding oral intake. Because FVC decreases about 10% in the supine position compared with sitting in nonobese individuals,8 diaphragmatic weakness may present with orthopnea and nocturnal desaturation, because the diaphragmatic contribution diminishes during sleep.2

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Respiratory Failure in Neuromuscular Disease 165 Patients should undergo immediate endotracheal intubation and mechanical venti-lation if they present with respiratory or cardiac arrest, shock, impaired conscious-ness, respiratory distress, or evidence of active aspiration caused by the weaknessof the upper airways. Patients with the weakness of the bulbar or respiratory muscleswho do not have these criteria for intubation should be closely monitored, both by clin-ical measures and when practical and possible in the clinical setting, by spirometryand measurements of respiratory muscle strength. Intubation may then becomenecessary if the respiratory status continues to deteriorate. When practical in the clinical situation, the pulmonary function tests (PFTs) to bemonitored at regular intervals are the FVC, negative inspiratory force (NIF, also knownas maximal inspiratory pressure [Pi max]) and positive expiratory force (PEF, ormaximal expiratory pressure [Pe max]), obtained by respiratory muscle strengthtesting. NIF predicts the ability to maintain adequate alveolar ventilation and thePEF predicts the ability to cough and clear the airways. These tests may be performedin a pulmonary function laboratory or at the bedside with suitable equipment. NIF canbe measured in the intubated patients in a critical care unit by qualified respiratorytherapists. It has been suggested that PEF is the most sensitive parameter to assessfor respiratory weakness in chronic NMD.9 However, FVC and NIF are simpler to use incritically ill patients, and assess the diaphragmatic function.6 FVC is normally about 60 to 70 mL/kg; specific values for a given patient are depen-dent on age, race, and height and should be expressed as a percentage of predictedfor a given patient.10 FVC of 30 mL/kg (50%–60% of predicted) is associated witha weak cough. Subjective dyspnea also occurs when FVC is less than 30 mL/kg,but there is variability between the patients based on the age and the presence ofunderlying cardiopulmonary disease.5,6 FVC less than 25 mL/kg is associated witha weak sigh (and development of atelectasis and hypoxemia) and FVC of 15 mL/kgor 1L (30%–35% of predicted) is considered an indication for mechanical ventila-tion2,6 in the appropriate clinical setting. FVC and NIF may be spuriously low if thereis significant weakness of the facial and bulbar muscles or if there is significant airleak around the device mouthpiece during testing. Tidal volume changes only slightlyin the early stages of respiratory failure but may decrease significantly with advancedneuromuscular weakness. Other less commonly used PFTs include peak cough flowrate (PCFR) and sniff nasal inspiratory pressure (SNIP).DIAGNOSTIC APPROACH TO THE UNDERLYING NMDHistoryA focused history should be obtained from the patient or family or by reviewing themedical records.1 The following aspects are especially important:1. A known underlying NMD: patients with amyotrophic lateral sclerosis (ALS) inexo- rably develop respiratory failure as a result of disease progression or aspiration. Patients with dystrophinopathy predictably become ventilator dependent later in the course, and myotonic dystrophy is associated with respiratory muscle weak- ness, as well as sleep-related breathing disorder and central hypoventilation.11 Previous episodes of generalized weakness may suggest hypokalemic periodic paralysis or myasthenia gravis (MG) crisis, and previous episodes of rhabdomyol- ysis may denote an underlying metabolic myopathy affecting the glycogen or lipid pathways, such as carnitine palmitoyl transferase type II (CPT-II) deficiency.2. A preexisting medical disease: an underlying cancer may suggest a paraneoplastic syndrome such as Lambert-Eaton myasthenic syndrome (LEMS), MG, or rarely, paraneoplastic motor neuronopathy. On the other hand, neoplastic infiltration of

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166 Rezania et al the nerve roots and the peripheral nerves often occurs with lymphoid malignancies and metastatic carcinoma. History of monoclonal gammopathy may be present in patients in chronic inflammatory demyelinating polyneuropathy (CIDP) and POEMS (polyneuropathy, organomegaly, endocrinopathy, M spike, skin changes). Patients with bone marrow transplantation are predisposed to autoimmune disease like MG ´ and Guillain-Barre syndrome (GBS). Human immunodeficiency virus (HIV) infection may be associated with GBS, CIDP, myositis, HIV myopathy, and polyradiculop- athy. Polyradiculopathy may be infectious (eg, cytomegalovirus) or malignant (eg, lymphoma). Critical illness neuropathy and myopathy (CIN/M) are the most common causes of weakness in critically ill patients in the intensive care unit (ICU) (see later discussion). 3. Illicit substance use and alcoholism could be associated with rhabdomyolysis. 4. Recent respiratory or gastrointestinal infections could be present in patients with GBS or MG exacerbation. Gastrointestinal symptoms are also seen in botulism, and abdominal pain often precedes the onset of respiratory weakness in acute intermittent porphyria. 5. History of recent major surgery may suggest GBS and CIN/M.12 6. Medications: a large proportion of patients with cancer or history of transplantation who are admitted to the ICU have been treated with neurotoxic medications (Box 1). However, toxic neuropathy is generally not a common cause of respiratory failure. Furthermore, several medications are implicated in precipitation of MG Box 1 Some of the drugs and toxins that may be associated with weakness as a result of polyneuropathy Vinca alkaloids (vincristine, vinblastine) Taxanes (taxol) Platinum compounds (cisplatin, oxaliplatin) Suramin Tacrolimus, sirolimus Thalidomide Bortezomib Amiodarone Metronidazole Nitrofurantoin Tumor necrosis factor a blockers Gold Metals (arsenic, lead, inorganic mercury, thallium) Hydrocarbons (n-hexane) Buckthorn Diphtheria Saxitoxin Tetrodotoxin Tick paralysis (North American type)

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Respiratory Failure in Neuromuscular Disease 167 crisis (Box 2). Barbiturates and several other antiepileptics, sulfonamides and other antibiotics, and a large number of other medications have been associated with precipitation of porphyria attack.7. Diet: fasting and low carbohydrate intake may precipitate a porphyria attack, as well as weakness and rhabdomyolysis in patients with a variety of metabolic muscle diseases such as CPT-II. Recent intake of a high-carbohydrate diet is often encountered before an episode of paralysis in hypokalemic periodic paralysis. Intake of canned food and seafood may precede botulism and saxitoxin poisoning, respectively. Intake of the buckthorn fruit has rarely been implicated in acute neuropathy.ExaminationThe accurate assessment of the muscle weakness in patients who are critically ill isoften limited by the lack of cooperation. In these patients, inspection may reveallack of spontaneous movements, muscle involuntary activity (fasciculations, myoky-mia), and muscle atrophy.13 Generalized areflexia and hypotonia suggest demyelin-ating neuropathy (ie, GBS) or polyradiculopathy. Myalgia and muscle tendernessmay represent myositis or rhabdomyolysis. Table 1 summarizes the patterns ofmuscle weakness in different classes of NMD.Electromyography and Nerve Conduction StudyElectromyography (EMG) is a valuable tool in the diagnosis of NMDs. It should prefer-ably be conducted in the neurophysiology laboratory, where the electrical interferenceis minimal. On the other hand, EMG is commonly conducted in critically ill patients inthe ICU. Table 2 summarizes the EMG characteristics of different categories of NMD.Other WorkupOther laboratory testing, including a nerve and muscle biopsy, is often needed toestablish the diagnosis of an NMD. Such a laboratory workup should be tailored to Box 2 Drugs associated with neuromuscular junction impairment or worsening of MG symptoms Antibiotics: aminoglycosides, colistin, polymyxin, macrolides, quinolones, imipenem, ciprofloxacin, tetracyclines Antiarrhythmics: procainamide, quinidine, lidocaine, trimethaphan Neuromuscular junction blockers (succinylcholine, vecuronium) Quinine Phenytoin Immunosuppressants: steroids, cyclosporine Antirheumatics: chloroquine, D-penicillamine Psychotropics: lithium, chlorpromazine Calcium channel blockers b-Blockers Magnesium Iodinated contrast

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168 Rezania et al Table 1 Clinical characteristics of different categories of NMD, based on the localization of the lesion in a motor unit Disease Category Clinical Characteristics Motor neuronopathy Muscle atrophy Fasciculations Frequent involvement of bulbar muscles Lack of sensory signs and symptoms DTRs: decreased or increased Æ pathologic reflexes Lack of ocular motor involvement until late in the course Polyradiculopathy and Loss of deep tendon reflexes neuropathy Motor and sensory impairment Æ Ocular motor involvement Æ Autonomic involvement Neuromuscular junction disorder Significant ocular motor involvement Frequent involvement of bulbar muscles Proximal / distal limb weakness Muscle atrophy usually not present DTRs: normal or decreased Myopathy Proximal / distal limb weakness DTRs: normal or decreased Æ Myalgia Æ Rhabdomyolysis Abbreviation: DTR, deep tendon reflex. an individual patient, based on the clinical and EMG findings. The clinical and labora- tory features of different NMDs are described in Tables 3–6. GBS GBS is an acute polyradiculoneuropathy caused by autoimmunity against the struc- tural components of the peripheral nerves.28 Acquired inflammatory demyelinating polyneuropathy (AIDP) is the most common subtype of GBS in the United States and Europe. Axonal subtypes, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy occur in less than 10% of cases in North Amer- ica and Europe.28,29 AMAN is particularly common in China, and another variant, Miller Fisher syndrome (MFS), is more prevalent in Japan.28,29 AIDP is characterized by progressive weakness, with maximal weakness present within 4 weeks, but usually within 2 weeks after the onset.30,31 The weakness typically affects both proximal and distal limb muscles and frequently the truncal and respiratory muscles. Reflexes are typically absent early in the course. Facial diplegia is seen in 70% of patients.29 Ocular motor involvement is less common, except in patients who are positive for the GQ1b antibody, including those with MFS. Sensory symptoms are commonly present, including severe pain in some patients.29 Dysautonomia, resulting from hypo- activity or hyperactivity of the sympathetic and parasympathetic systems, occurs in about two-thirds of patients. Although mild in most patients, dysautonomia can be severe and even fatal. The symptoms may include severe fluctuations in blood pres- sure, heart arrhythmia, abnormal pupillary response, bladder atonia, and ileus.29,32 A history of a respiratory or gastrointestinal tract infection 3 weeks or less before the onset is present in about two-thirds of patients with AIDP.29 Campylobacter jejuni is the most commonly encountered pathogen, and is associated with seropositivity to IgG GM1, an axonal form, and less favorable prognosis.33–36 Cytomegalovirus is the

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Respiratory Failure in Neuromuscular Disease 173 Table 4 (continued) Neuromuscular Treatments (Other than Close Junction Disorder Clinical Features Monitoring and Respiratory Care) Tick paralysis Ixodes holocyclus (marsupial tick) Antitoxin to be injected before Australian type87 Rapidly progressive ascending tick removal paralysis, with early cranial More severe, and longer time to nerve involvement recovery than the North Respiratory failure common and American type potentially fatal ICU admission and respiratory EMG: low motor amplitudes, support in the acute stage normal sensory responses; normal repetitive stimulation Possible mechanism: interference by neurotoxin with ACh release an NMJ (similar to botulinum toxin) Prolonged Underlying kidney or liver failure, Avoidance of use of neuromuscular hypermagnesemia, medication neuromuscular blocker block88 interaction (eg, sevoflurane), cholinesterase or pseudocholinesterase deficiency Use of a neuromuscular blocker (eg, mivacurium, rapacuronium) Generalized weakness, ophthalmoparesis, ptosis, failure to weanAbbreviations: ACh, acetylcholine; BTX, bungarotoxin; DAP, diaminopyridine; NMJ, neuromuscularjunction.at the same time if possible, because it may be more sensitive to declines in respira-tory function. The patients with significant respiratory muscle weakness may deteriorate clinically, asshown by distress, fatigue, accessory muscle use, and thoracoabdominal dyssynchrony,before such deterioration is reflected in either arterial blood gas (ABG) or pulmonary func-tion measurements. Therefore, intubation, either elective or emergent, is a bedside clin-ical judgment. Because emergency intubation substantially increases the risk of complicationssuch as aspiration and hypoxemia, it is essential to anticipate the need for intubationand mechanical ventilation and proceed with elective intubation in selected patients.Criteria proposed for elective intubation and MV in patients with GBS include signifi-cant respiratory distress, fatigue, sweating, tachycardia, active aspiration, and FVC of10 to 12 mL/kg (30%–35% of predicted), and PaCO2 greater than 50 mm Hg. Electiveintubation should be considered in the presence of a higher FVC if the condition israpidly deteriorating, if there is inefficient cough, inability to clear bronchial secretionsdespite vigorous chest physiotherapy,38,39,41 or if the patient has a significantconcomitant morbidity such as active cardiac ischemia or heart failure. Predictive parameters for mechanical ventilation in GBS include rapidly progressivecourse as manifested by time to peak disability less than 7 days, time from the onset ofsymptoms to hospitalization less than 7 days, and more than 30% reduction of vitalcapacity, NIF, and PEF.40,42 Significant bulbar dysfunction, facial weakness, impairedcough, dysautonomia, and inability to lift the elbow or head off the bed are other sug-gested predictors of need for mechanical ventilation. On the other hand, an FVC less

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Respiratory Failure in Neuromuscular Disease 175than 20 mL/kg, NIF less than negative 30 cm H2O and PEF less than 40 cm H2O (20/30/40 rule) during the course of hospitalization are other PFT parameters that havebeen suggested to predict intubation and mechanical ventilation.42,43 Noninvasive, positive pressure ventilation (NIV or NIPPV) is not a good choice inpatients with respiratory failure and significant bulbar muscle weakness, becausethere is increased risk of aspiration or collapse of the upper airways.2 NIV shouldalso be avoided in patients who are likely to need a long duration of respiratorysupport. Other important supportive management issues include deep vein throm-bosis and peptic ulcer disease prophylaxis, and appropriate treatment of the cardiacarrhythmias, fluctuations in the blood pressure, ileus, and urinary retention. Plasma exchange (PE) and intravenous immunoglobulins (IVIG) are both proved tobe effective in the treatment of GBS.28,44 PE is more effective when it is given early inthe course, and the usual regimen is a total exchange of about 5 plasma volumes of 50mL/kg during 1 to 2 weeks.28,45 IVIG has replaced PE as the preferred method of treat-ment in many hospitals, after a large randomized clinical trial showed its equal efficacyto PE.46 The usual dose is 2 g/kg over a 3 to 5-day period.45 The mortality of GBS isestimated at 3% to 10%; the most common causes of death are the complications ofdysautonomia and respiratory failure.29,32 Table 3 summarizes the clinical and para-clinical features of some of the other neuropathies that could be associated with respi-ratory failure.GENERALIZED MGGeneralized MG is a commonly encountered neuromuscular cause of respiratoryfailure. Involvement of the facial and oropharyngeal muscles happens during thecourse of the disease in most patients, causing facial weakness, dysphagia, anddysarthria (nasal speech). MG crisis is referred to exacerbation of the generalizedweakness, with associated respiratory insufficiency and the need for mechanicalventilation. MG rarely presents with isolated stridor or respiratory failure.47–49 Thecourse of MG is unpredictable, especially in the first 2 years of diagnosis. MG crisisoccurs in approximately 15% to 20% of patients some time during the course, butmost often during the first year after the onset of symptoms.50 MG crisis may beprecipitated by the disease progression, treatment with high-dose steroids, anticho-linesterases, and other medications that affect the neuromuscular transmission (seeTable 3).3,50,51 Intercurrent infections, pregnancy, surgery, and other sorts of stress(including emotional) are other causes of MG crisis. MG diagnosis is usually made based on the clinical grounds and seropositivity to theacetylcholine receptors (AChR) autoantibodies, present in about 85% of the general-ized cases.52 Antibodies to the muscle specific kinase are found in about 40% of theseronegative patients.53 EMG is useful to differentiate MG from neuropathies such asGBS, myopathies, motor neuron diseases (MNDs), and other neuromuscular transmis-sion diseases such as LEMS and prolonged effect of the neuromuscular blockers (seeTable 1). The edrophonium (Tensilon) test can be used at the bedside to diagnoseMG.52,54 Edrophonium is given intravenously, and the patient is watched for imme-diate improvement of the MG symptoms, usually ptosis or ocular movements. If theappropriate target symptoms are present, the sensitivity is 71% to 95%.54 Cardiacmonitoring is strongly recommended, because there is a low risk of serious sideeffects like bradycardia and asystole. It has been suggested that because of itsmaximum effect at 15 to 30 minutes, 2 mg of intramuscular neostigmine could providebetter diagnostic results in patients with respiratory weakness, because the PFT datacan be repeated during that interval.6

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178 Rezania et al Respiratory failure in MG may present with tachycardia, anxiety, restlessness, and tachypnea in the early stage. Later in the course and with worsening hypoxemia and the emergence of hypercapnia, patients develop cyanosis, encephalopathy, and headaches. MG patients with questionable status should be closely monitored in the ICU with repeated clinical evaluation as well as bedside FVC and NIF.5 However, given the fluctuating nature of the weakness, it is often difficult to predict the need for mechanical ventilation in MG, even with close monitoring.2,55 An ABG measurement should be obtained if there is suspicion of evolving respiratory failure. Intubation is rec- ommended with marginal and declining respiratory status, FVC less than 15 mL/kg, PaO2 less than 60 mm Hg and PaCO2 greater than 50 mm Hg.6 Oral intake should be stopped, and intubation should also be considered in patients with aspiration or signif- icant weakness of the oropharyngeal muscles. In a retrospective study, the mortality of MG crisis was 4% and the parameters that predicted prolonged intubation included a preintubation bicarbonate level greater than 30 mg/dL,peak vital capacity less than 25 mL/kg on day 1 to 6 after intubation, and age older than 50 years.50 The use of NIV (intermittent bilevel positive airway pressure [BIPAP]) early in the course of the MG crisis may prevent the development of atelectasis and lead to a lesser need for intubation and mechanical ventilation. In 2 retrospective studies on respiratory failure in MG, BIPAP prevented intubation and mechanical ventilation in 60% to 70% of the trials.56,57 Hypercapnia (a PCO2 45 mm Hg) was a strong predictor of the failure of BIPAP in one of those studies.57 PE and IVIG with the same dose mentioned under GBS have been shown to be effective in myasthenic crisis.58 Although PE was more effective for improving the respiratory status than IVIG in a study, it was also associated with more side effects and increased length of ICU stay.59 Starting a high dose of corticosteroids is a potential cause of MG crisis, and should be avoided unless the patient is already on mechanical ventilation. If the patient is on a low dose of prednisone, the dose should be increased, preferably after the respiratory function has started to improve with either PE or IVIG. Anticholinesterase inhibitors such as pyridostigmine should be withheld in patients on mechanical ventilation for the potential cardiovascular side effects such as arrhyth- mias, increasing bronchial secretions, and increased airway resistance.58 Pyridostig- mine, which is also available in the intravenous form, may be restarted when the patient is being weaned off. It can be started at 30 mg orally every 3 to 4 hours, and increased to 60 mg every 3 to 4 hours. Higher doses (up to 120 mg every 3–4 hours) are sometimes used; however, higher doses often do not improve the symptoms, and the weakness may paradoxically deteriorate.58 Table 4 summarizes the clinical and laboratory characteristics of other more commonly encountered neuromuscular junc- tion transmission diseases. ALS MND is characterized by progressive degeneration of the motor neurons. The less common variants of MND (spinal muscular atrophy and spinobulbar muscular atrophy) are diseases of the lower motor neurons (which are located in the motor brainstem nuclei and the anterior horns of the spinal cord). On the other hand, ALS is character- ized by the progressive degeneration of the lower and upper motor neurons. Respira- tory failure emerges in almost all patients with ALS, and is the cause of death in most of these patients.60,61 Respiratory muscle weakness is predominantly secondary to diffuse denervation (lower MND); however, upper motor neuron impairment is also implicated in the respiratory symptoms in ALS.62,63 Bulbar muscle dysfunction caused by lower motor neuron (bulbar palsy) or upper motor neuron (pseudobulbar palsy)

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Respiratory Failure in Neuromuscular Disease 179disease, also invariably complicates the clinical course of ALS.64 Bulbar-onset ALS ismore common in older patients; 43% of patients with ALS older than 70 years pre-sented with bulbar symptoms in a study.65 Bulbar weakness results in aspirationand impaired cough, as well as malnutrition, which leads to further weakness andatrophy of the respiratory muscles.64 Early symptoms of respiratory failure in ALSinclude exertional dyspnea, orthopnea, frequent nocturnal arousals, daytime somno-lence, morning headaches, and impaired memory and concentration.63 Because respiratory failure may even occur early in the course of ALS, the treatmentplan and the patient’s wish for intubation and mechanical ventilation should be discussedbefore an emergency situation arises.7 Patients with ALS should be closely monitoredwith PFTs such as supine and upright FVC, PEF, NIF, and PCFR.7 The efficacy of theairway mucous clearance is largely determined by the strength of the cough as assessedby the PCFR.64,66 These tests may be spuriously low when bulbar and facial weakness ispresent, and when there is inadequate control of the voluntary respiratory musclesbecause of upper motor neuron involvement. SNIP is another method that can be effec-tively used in patients with significant bulbar weakness, because it does not requirea tight seal around a mouthpiece.63 SNIP has been shown to correlate with the trans-diaphragmatic pressure, and SNIP less than 40 cm H2O correlates with nocturnal hypox-emia.67 Nighttime pulse oximetry may also provide evidence for intermittent nocturnalhypoventilation, because the hypoventilation generally deteriorates during sleep. The timely institution of adequate nutrition through percutaneous endoscopic gas-trostomy has been shown to improve the survival and the quality of life in patients withALS.61 The procedure-related morbidity is substantially lower when percutaneousendoscopic gastrostomy is performed with FVC greater than 50% predicted andSNIP greater than 40 cm H2O; and the rate of procedure-associated complications(including intubation and mechanical ventilation) substantially increases in patientswith more advanced respiratory failure.61,67 The use of NIV has been recommendedwith the presence of signs and symptoms of respiratory failure, greater than 1 minuteof nocturnal O2 desaturation of less than 90%, FVC less than 50%, SNIP less than 40cm H2O, and PCFR less than 270 L/min.63,68 Aspiration and increased secretions asa result of bulbar weakness may result in difficulties in the use of NIV in patientswith ALS. Because mucous plugging could result in serious complications such asatelectasis and pneumonia, frequent chest physiotherapy, frequent suctioning, anduse of assistive cough devices are recommended in patients with a weak cough.63 Because continuous positive airway pressure causes increased workload on thealready weak respiratory muscles, it is better avoided in patients with ALS.7 Cautionshould also be exercised in the use of medications that suppress the respiratory drive(such as benzodiazepines and narcotics). The use of nocturnal supplemental oxygenin patients with significant respiratory muscle weakness (including ALS) has also beenshown to suppress the respiratory drive and cause hypercapnia.63,69RESPIRATORY WEAKNESS IN THE ICUIn patients with respiratory muscle weakness in the ICU, it should first be determinedwhether the weakness preceded (and led to) the ICU admission. GBS and MG crisisare the most commonly encountered acute NMDs that result in ICU admission. Onthe other hand, Critical Illness Myopathy and Polyneuropathy (CIM and P) accountfor most patients who develop weakness (or cannot be weaned from the ventilator)after being admitted to the ICU for another reason. In a retrospective study on 92 ICU patients who underwent EMG, 28% had a primaryNMD (GBS, MG, and MND) that resulted in the ICU admission. CIM and P accounted

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180 Rezania et al for 42% and 13% of the cases, respectively.70 Electrophysiologic evidence for CIM and P was present in 50% of ICU patients with a stay of more than 3 days in another study.71 Of patients with ICU stay of more than 1 week, 50% to 70% develop clinical CIM and P; this figure may reach 100% in patients with a long ICU stay with sepsis and end-organ damage.71 CIM and P often emerges in the setting of treatment with high-dose corticosteroids and neuromuscular blockers. Other risk factors include sepsis, long ICU stay, encephalopathy, and need for vasopressor support.71,72 The clinical picture consists of generalized weakness, lack of tolerance of weaning from the ventilator when the patient is off sedation, and lack of cardiopulmonary explanation. Examination reveals flaccidity and hyporeflexia, and muscle atrophy can be prominent in chronic cases. Muscle atrophy results in the prominence of the hand tendons and the tibia in patients with severe critical illness polyneuropathy (CIP).13 Facial weakness and oph- thalmoparesis are rare and these features point to other differential diagnoses (ie, MG, prolonged neuromuscular blockade, GBS).71 Examination of the sensation is usually complicated by encephalopathy and sedation, but there is a stocking-gloves decrease of sensation when CIP is present.13 Creatine phosphokinase (CPK) level was markedly increased in a retrospective study in about 50% during the first 5 days after the onset of the weakness, with subsequent gradual normalization.73 The nerve conduction study may be normal, or shows abnormally low compound muscle action potential ampli- tudes in CIM. It reveals an axonal sensorimotor neuropathy in CIP. Abnormal sponta- neous activity is seen in some cases of myopathy, and is uniformly present in the more distal muscles in CIP.71 Direct muscle stimulation has been used to distinguish CIP and CIM (muscle is inexcitable in CIM).74 If a muscle biopsy is performed, it may show myosin loss, myofiber atrophy, or a necrotizing myopathy (myofiber necrosis, vacuoli- zation, and phagocytosis).71 Minimizing the use of high doses of steroids and neuro- muscular blocking agents and aggressive insulin treatment (keeping the blood sugar at 80 to 110 mg/dL) have been suggested to reduce the incidence of CIM and CIP. REFERENCES 1. Bella I, Chad DA. Neuromuscular disorders and acute respiratory failure. Neurol Clin 1998;16:391. 2. Mehta S. Neuromuscular disease causing acute respiratory failure. Respir Care 2006;51:1016. 3. Yavagal DR, Mayer SA. Respiratory complications of rapidly progressive neuro- ´ muscular syndromes: Guillain-Barre syndrome and myasthenia gravis. Semin Respir Crit Care Med 2002;23:221. 4. Teramoto K, Kuwabara M, Matsubara Y. Respiratory failure due to vocal cord paresis in myasthenia gravis. Respiration 2002;69:280. ´ 5. Green DM. Weakness in the ICU: Guillain-Barre syndrome, myasthenia gravis, and critical illness polyneuropathy/myopathy. Neurologist 2005;11:338. 6. Ropper AH, Gress DR, Diringer MN, et al. Neurological and neurosurgical inten- sive care. 4th edition. Philadelphia: Lippincott Williams Wilkins; 2004. 7. Oppenheimer EA. Treating respiratory failure in ALS: the details are becoming clearer. J Neurol Sci 2003;209:1. 8. Vilke GM, Chan TC, Neuman T, et al. Spirometry in normal subjects in sitting, prone, and supine positions. Respir Care 2000;45:407. 9. Griggs RC, Donohoe KM, Utell MJ, et al. Evaluation of pulmonary function in neuromuscular disease. Arch Neurol 1981;38:9. 10. Stanojevic S, Wade A, Stocks J, et al. Reference ranges for spirometry across all ages: a new approach. Am J Respir Crit Care Med 2008;177:253.